An atomic scale mechanism for the antimalarial action of chloroquine from density functional theory calculations

Abstract

The X-ray crystal structures of complexes between the antimalarial drugs quinine,

Computational insights into the inhibition of β-haematin crystallization by antimalarial drugs

“…Recently, Fielding et al have concluded from DFT calculations that MQ could stabilize a hydroxy complex of FePPIX, formulated as [FePPIXH 2 (OH)(MQH)] + , perhaps as an intermediate on the path to the experimentally characterized alkoxide complex. 33 Apart from the overall positive charge, this complex is analogous to the neutral 1 : 1 complex of CQ that we postulated previously, 28 and the hydroxy complexes of several other drugs as discussed below.…”

“…We have previously modelled the FePPIX-HN complex by DFT, and found that the intermolecular hydrogen bond to propionate observed in the crystal structure can be replaced by an intramolecular equivalent in the isolated complex. 28 In the present work, we have extended our studies to the analogous complexes of MQ and LM. The structures of all three DFT model complexes are shown in Fig.…”

“…This possibility has been demonstrated experimentally by the X-ray crystal structures of FePPIX complexes with QN, QD, MQ, and HN. [16][17][18] Complex B is an analogous 1 : 1 complex, in which the Fe-O bond is supplied by hydroxide; we have previously postulated such a complex for CQ, 28 although there is no experimental evidence for this possibility at present. Finally, complex C has a 2 : 1 FePPIX : drug stoichiometry and includes a bridging oxo ligand; this type of structure has been demonstrated in solution for CQ.…”

“…1). 28 Formation of this 1 : 1 complex is predicted to be energetically neutral in water, but favourable in n-octanol (see Table 4; as usual, these values do not include the π-π stacking contribution, which is expected to be ∼3.9 kcal mol −1 for the quinoline group in water, 30 and rather less in n-octanol 31 ). This 1 : 1 complex is currently unknown from experiment; however a related 2 : 1, oxo bridged complex has recently been experimentally characterized in solution.…”

“…With respect to CQ, we have previously used DFT calculations to postulate a theoretical 1 : 1 complex between CQ and FePPIX, in which the drug stabilizes the coordination of a hydroxide ligand, generated from water, at the iron(III) centre (Scheme 3, generic complex B). 28 The recruitment of water to form a hydroxide ligand with transfer of the proton to the tertiary amine of CQ would then be analogous to the action of the alcohol-containing drugs, which act as alkoxide ligands to FePPIX with internal proton transfer to the amine. Meanwhile, as discussed above, experimental studies have confirmed that CQ can indeed recruit a water molecule to support an Fe-O bonded complex with FePPIX, however the observed FePPIX : drug stoichiometry is 2 : 1 rather than 1 : 1 (Scheme 3, complex C).…”